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Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p p = 0.005). Time-to-best response (TTBR) and ORR (p p p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

Dataset of 65 tumor samples.

Expression of the 23 genes and signatures across the 3 cancer groups in the nCounter-based dataset

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD Cancer Res; 77(13); 3540–50. ©2017 AACR.

BACKGROUND: Analysis of circulating free DNA (cfDNA) by the real-time PCR cobas(®) EGFR Mutation Test v2 (cobas(®) EGFR Test) is a diagnostic approach used in clinical practice for the characterization of advanced non-small cell lung cancer (NSCLC) patients. The test additionally outputs a semiquantitative index (SQI) which reflects the proportion of mutated versus wild-type copies of the EGFR gene in cfDNA with potential use as a biomarker. CfDNA concentration and cfDNA fragmentation pattern have also shown potential utility as biomarkers for cancer patients. We evaluated the implementation of EGFR testing and cfDNA related parameters in NSCLC patients in routine clinical setting as biomarkers for disease stage and diagnosis. METHODS: A prospective cohort of 173 locally advanced or metastatic NSCLC TKI-naïve patients analyzed by the cobas(®) EGFR Test were included in the study. Reproducibility of the test was assessed in 56 patients. The concentration of cfDNA and fragment size pattern was measured using fluorometry and microchip electrophoresis respectively. RESULTS: The test showed high diagnostic accuracy when compared to the gold standard of biopsy tumor tissue testing. The SQI value showed a moderate reproducibility (r(2)=0.70) and did not correlate with cfDNA concentration (r(2)=0.17, P=0.28) or disease stage (stage III patients SQI =9.1±3.1 and stage IV patients SQI =11.5±4.8, P=0.41). We found differences in SQI values according to the type of EGFR mutation (Ex19Del mutations, SQI =13.6; p.L858R, SQI =8.88; P=0.001). Stage IV patients had higher concentrations of cfDNA (P

Background ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer. Patients and methods This first-in-human trial consisted of an escalation phase (3 + 3 design), followed by an expansion phase, to assess safety and tolerability of ABTL0812. Secondary objectives were determining the recommended phase II dose (RP2D), clinical antitumour activity, pharmacokinetics (PK) and pharmacodynamics (PD). Results A total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500 mg once a day to 2000 mg twice a day) and fourteen in the expansion phase (dosed with 1300 mg three times a day). No maximum tolerated dose was attained, and RP2D was determined by PK/PD modelling. Most drug-related adverse events were gastrointestinal grade I–II. Correlation between drug levels and pAkt/Akt ratio was found. Two cases of long-term (>1 year) stable disease were observed. Conclusions ABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300 mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed. Clinical trial registration number NCT02201823.

Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients’ clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months, p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3, p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.

4152 Background: Despite huge efforts patients (pts) with advanced PDAC, still have a dismal long-term prognosis. The lack of available good-quality tissue samples for next generation sequencing (NGS) prevents from finding actionable alterations that could guide personalized treatments. Circulating tumor DNA (ctDNA) provides a non-invasive method for obtaining molecular information with therapeutic potential. Here, we present prospective data of ctDNA sequencing in pts with PDAC. Methods: We collected a single blood sample from advanced PDAC pts at any line of treatment (Tx) and at least 10 days apart from their last therapy. The samples were analyzed by Guardant360 plasma-based NGS, a standardized assay which covers microsatellite instability [MSI] evaluation and analysis of all four types of somatic alterations in 74 genes. Alterations were reported either as pathogenic or non-pathogenic. We classified each gene alteration according to the different OncoKB therapeutic levels of evidence [LE]. Additionally, we gathered the dates of both blood collection and molecular report. In case the molecular report showed no tumor-related alterations, it was interpreted as either absence of detectable mutations or low ctDNA levels, which would translate low disease burden or pts responding to therapy. Demographic and clinical data have been accessed from the medical records. Results: From 08/2019 to 09/2021 we collected blood samples from 94 PDAC pts. 56% of them were male and 53% were >65 years old. At the time of sample collection, nearly all pts were metastatic (98%). Regarding previous lines of Tx, 57% pts were Tx naïve; 10% were receiving active systemic Tx and 33% had experienced disease progression. Molecular reports were available in an average of 9.1 days. A total of 243 gene alterations were detected, having 94% of pts at least 1 genomic alteration, which was pathogenic in 69% of the cases (see Table). There were no pathogenic alterations ranked as OncoKB LE 1-2 ( MSI or NTRK). Seventy alterations (30%) were ranked as OncoKB LE 3A and 4 ( ARID1A, BRAC2, CDKN2A, KRAS). Three of these pts were treated with PARP inhibitors due to the presence of BRCA2 mutations. No ctDNA was detected in 15 pts (16%), despite being the sample collected >10 days from receiving their last Tx. Of these, 11 had low tumor burden (only peritoneal or lung metastases) and 4 had documented response to the Tx by the time the samples were collected. Conclusions: Real-time and prospective genomic profiling of pts with advanced PDAC using ctDNA is feasible and conveniently fast, which would allow its role in identifying and developing therapeutic targets for approved Tx or clinical trial treatments. [Table: see text]

Since the approval of immune checkpoint anti-programmed cell death protein 1 antibodies (pembrolizumab and nivolumab) and anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) in combination or monotherapy, significant advances have been made in the treatment of metastatic melanoma. The nonspecific immune stimulation resulting from these drugs can case a wide range of side effects in many organs including the nervous system, named immune-related adverse events. Few immune-related encephalitis associated with these antibodies have been described in the literature. It is a rare complication (

Objectives: In the EXTREME trial, a combination of cisplatin or carboplatin plus 5-fluorouracil (5-FU) and cetuximab was superior to cisplatin/carboplatin plus 5-FU for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). With the aim of improving fluoropyrimidine-related tolerance without decreasing its efficacy, the safety and efficacy of carboplatin plus the oral fluoropyrimidine tegafur and cetuximab were investigated. Methods: A retrospective analysis of 104 patients with recurrent or metastatic HNSCC was conducted. Patients were treated with carboplatin (area under the curve: 5 mg/mL/min) on day 1, oral tegafur (250 mg/m2 twice daily) for 21 consecutive days, and cetuximab (400 mg/m2 as an initial 2-hour intravenous infusion, then 250 mg/m2 as a 1-hour weekly infusion for 3 weeks) for ≤6 cycles. Patients who responded to the therapy then received weekly cetuximab maintenance therapy. Results: Treatment was well tolerated with a high level of compliance (relative dose intensity: 96%, 88%, and 81% for carboplatin, tegafur, and cetuximab, respectively). Grade 3-4 adverse events (AEs) were observed in 38% of patients (skin reactions in 17% of patients, anemia 4%, and neutropenia 3%). Grade 1-2 AEs included skin reactions (52% of patients), hypomagnesemia (20%), asthenia (19%), and anemia (13%). No venous thrombosis related to chemotherapy perfusion was observed. Over a median follow-up of 21 months, the median overall and progression-free survival were 11 and 6 months, respectively, and the overall response rate was 35%. Conclusions: Carboplatin plus oral tegafur and cetuximab is a safe, well-tolerated first-line therapy for recurrent or metastatic HNSCC.

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD

Introduction Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. Methods We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. Results The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration. Discussion We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017.

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation.

3060 Background: Genetic profiling (GP) is essential not only for understanding tumor biology but also helps to identify potential genes for targeted therapies. At the same time, selected CT provide an individual genomic profile panel during the pre-screening phase. Here, we demonstrate our experience using these panels. Methods: We selected 14 CT from our Early Drug Development Clinical Trial Unit at Hospital Clinic of Barcelona that included analysis of gene panels in tumor (Foundation One, ArcherDX, Therascreen and Sophia Genetics) or plasma (Resolution Bioscience ctDx). These panels analyzed mutations, fusions, amplifications, microsatellite instability (MSI) and tumor mutational burden (TMB), among others. We collected information about types of cancers, molecular alterations and therapies chosen according to the results of GP. The platform OncoKB (Chakravarty JCO PO, 2017) was used to define genes with potential target therapies and levels of evidence (LE) for those targets (from LE 1 –FDA-recognized biomarker predictive of response to an FDA-approved drug- to LE 4 –Compelling biological evidence supports the biomarker as being predictive of response to a drug). Descriptive statistics were used. Results: From March 2017 to January 2021 we analyzed samples from 410 patients (pts) with CNS (19.3%), urothelial (18.3%), prostate (17.6%), breast (15.4%), ovarian (9.3%), esophageal and gastric (5.4%), colorectal (4.4%), pancreas (2.7%), endometrial (2.4%), cholangiocarcinoma (1.2%), cervix (1%), HNSCC (1%), renal (1%), lung (0.5%), liver (0.2%) fallopian tube (0.2%) and paraganglioma (0.2%). 352 pts (85.8%) had at least 1 genetic alteration. The most frequently altered genes were TP53 (153 pts, 46.2%), INSR (19 pts, 22.8%), TERT (76 pts, 22%), CDKN2A (65 pts, 19.9%), FAM175A (11 pts, 19.3%), CDKN2B (54 pts, 18.1%), MLL2 (53 pts, 17.7%), PTEN (52 pts, 16%), MTAP (45 pts, 15.7%), PIK3CA (52 pts, 15%) and ATM (55 pts, 14.4%). TMB ranged from 0 to 76.9 mut/Mb (median 2.5 mut/Mb). MSI was found in 3 pts (1.5%). 196 pts (47.1%) had an OncoKB LE 1 alteration, 105 pts (25.6%) if we restrict the options to their specific cancer type. 16 pts (3.9%) received a matched therapy: 6 pts received an off-label drug, 6 pts were included in the same CT for which the pre-screening was performed and 4 pts were included in a different CT. Additionally, 13 pts (3.2%) received a matched therapy either with OncoKB LE 4 (5 pts received an off-label drug and 3 were included in a different CT) or not included in OncoKB (8 pts included in the same CT of the pre-screening). As a whole, 29 pts (7.1%) received a matched drug according to their genomic results. Conclusions: Comprehensive gene panel testing offered through CT allows the identification of targets to enroll pts, although the recruitment was 1.5%. However, 7.1% of the pts received a matched therapy due to the molecular information of these gene panels.

Aim: While both efficacy and safety of anti-PD-1 agents seem to be independent of previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis describes the efficacy and safety of sequential therapy with ipilimumab in patients with metastatic melanoma who progressed on anti-PD-1 antibody. Methods: Nine patients who progressed on anti-PD-1 therapy received four cycles of ipilimumab 3 mg/kg every 3 weeks. Results: Two out of nine patients (2/9; 22.2%) showed a partial response, and seven patients (7/9; 77.8%) experienced disease progression. Median progression-free survival was 3.14 months (95% CI: 2.56–3.71), and the median overall survival since the start of anti-PD-1 therapy was 16.8 months (95% CI: 8.1–25.4). Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported. Conclusion: In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.

El reconocimiento de los pueblos indígenas en el sistema normativo vigente, empezando por la definición del Estado Colombiano como multiétnico y pluricultural, ha sido el resultado de resistencias, re-existencias y luchas históricas de los pueblos por mantener viva su tradición y por apropiar a su cultura, lo necesario para perdurar en el espacio y el tiempo histórico contemporáneos, marcados por el desconocimiento, la marginación e imposición de valores, creencias y principios ajenos a sus culturas. En consecuencia, derivado del interés por establecer el estado del conocimiento a partir de los estudios realizados en la Maestría en Educación desde la Diversidad [MED], se realizó una investigación con tres fases: exploratoria-descriptiva, analítico-sintética e interpretativa. Los hallazgos muestran una tendencia a reconocer en el mundo indígena condiciones de vulnerabilidad y a recorrer modos como el estado ha atendido y puede atender tal vulnerabilidad, así como a reconocer el valor de una educación pertinente para tender puentes entre el mundo indígena y los otros colectivos en Colombia, como formas de establecer relaciones de unidad en la diversidad e ir configurando modos de vida en orden al reconocimiento mutuo entre grupos.

Immunotherapy (IT) agents and BRAF inhibitors (BRAFi) are effective treatments for patients with advanced BRAF-mutant melanoma although the optimal sequence remains to be elucidated. The aim of this study was to compare the outcomes of two different cohorts of patients treated with BRAFi first, then IT or the reverse sequence.This is a retrospective study on two groups of patients: a cohort was treated first with BRAFi followed by immunotherapy (BRAFi-IT) and the other cohort with the reverse sequence (IT-BRAFi). Baseline characteristics and clinical outcomes were compared between the two cohorts.A total of 25 patients were included in the study. Sixteen patients were given BRAFi-IT sequence and nine received IT-BRAFi sequence. No differences were observed in the characteristics of patients prior to each treatment between cohorts. Objective response rate (ORR) achieved by BRAFi were not different among groups. ORR achieved by IT was higher when administered after BRAFi (43.8 vs 0 %). Survival rates at 1-2 years were similar in both cohorts and median overall survival was not different for BRAFi-IT and IT-BRAFi (log rank test p = 0.97).No differences were observed in OS between the two cohorts. These results support the indistinct use of IT or BRAFi as initial treatment in patients with metastatic BRAF-mutant melanoma, although higher rate of response to IT was observed when administered after BRAFi. Prospective randomized clinical trials are needed on this issue.

526 Background: CX-2009 is a PROBODY drug conjugate (PDC) directed against CD166 (ALCAM) and conjugated to DM4, a potent microtubule inhibitor (MTI). CD166 is overexpressed in carcinomas but is also ubiquitously expressed in normal epithelium and thus has not been previously considered a viable target for a traditional antibody drug conjugate. PDCs have a peptide mask that blocks normal tissue binding and can be removed by tumor-associated proteases, thereby limiting off-tumor/on-target binding. CX-2009 demonstrated preclinical activity in multiple solid tumor models. Here we report results of the first in human study in patients with advanced cancer. Methods: In this phase I multi-part dose-escalation study, pts with advanced solid tumors received CX-2009 0.25–10 mpk IV every 14 or 21 days (Q2W or Q3W). Tumor types were selected based on expected high CD166 expression and MTI sensitivity. Results: The dose-escalation phase of the trial enrolled 43 pts; 49 additional pts were subsequently enrolled between 4–10 mpk to collect biomarker data and define the recommended phase II dose (RP2D), for a total of 92 pts as of 30 Nov 2019 (39 pts with breast cancer [BC], 22 ovarian [OC], 12 non-small cell lung [NSCLC], 9 head/neck squamous cell [HNSCC], 10 other) with a median of 6 (range 1–19) prior therapies. Median number of CX-2009 doses was 2 (range, 1–15). For Q3W dosing, one dose limiting toxicity (DLT; grade 3 vomiting) was observed at 8 mpk; MTD was not reached up to 10 mpk. The RP2D for Q3W schedule was 7 mpk based on safety, dose-response, and population pharmacokinetic simulations. Q2W dosing continues; DLTs were observed at 6 mpk. Common treatment-related adverse events (TRAEs) at 7 mpk (n=9) were nausea (44%), fatigue, infusion-related reactions (both 33%), vomiting and arthralgias (both 22%). Grade 3 TRAEs occurred in 2 pts (nausea/vomiting; peripheral neuropathy). No pts discontinued at 7 mpk due to TRAEs. Ocular toxicity was dose dependent; mild to moderate reversible keratitis/blurred vision was seen in 3 pts at 7 mpk and mitigated by ocular prophylaxis. Partial responses were seen in 8 pts (2 confirmed, both HR+/HER2- BC) treated between 4–10 mpk, including BC (n=5), OC (n=2), and HNSCC (n=1). SD (≥1 on-study scan) was observed in 21 pts, 5 had SD ≥3 mos. Conclusions: CX-2009 at 7 mpk is the RP2D on Q3W schedule. Phase II expansion has begun in pts with HR+/HER2- BC. The Q2W schedule will continue to enroll pts to define the RP2D. CX-2009 will also be studied in combination with CX-072, a PD-L1 PROBODY therapeutic ( NCT03149549 ) Clinical trial information: NCT03149549 .

164 Background: Cancer cells may metabolize glutamine to fulfill their metabolic needs. In prostate cancer it has been shown that androgen receptor signaling promotes glutamine metabolism by increasing the expression of the glutamine transporters, and that stromal glutamine may promote tumor growth. Methods: We retrospectively tested glutamine levels in frozen plasma samples from mCRPC patients treated with taxanes, which were included in a prospective biomarker study in our institution. Glutamine levels were determined by a bioluminescent assay. Optimal cut-offs for glutamine levels were assessed using maximally selected log-rank statistics to determine low and high level groups. Pre-treatment glutamine level was correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Seventy eight mCRPC patients treated with taxanes were included. Median age was 70.3 (55.8-83.5) years and median follow-up was 13.1 (0.2-53.9) months. Glutamine was tested in 88 plasma samples: 69 from pre-docetaxel and 19 pre-cabazitaxel treatment (10 patients had both samples). High glutamine levels significantly correlated with worst PSA-progression-free survival (PFS) (median 2.8 vs 4.7 months, hazard ratio [HR] 1.8, 95%CI 1.1-2.7, P= 0.012) and overall survival (OS) (median 12.4 vs 20.4, HR 2, 95%CI 1.2-3.3, P= 0.006). In a multivariate analysis, high plasma glutamine levels were independently associated with shorter PSA-PFS (HR 2.3, 95%CI 1.4-3.7, P< 0.001) and OS (HR 2.2, 95%CI 1.3-3.7, P= 0.003). Patients with high glutamine levels were more likely to present PSA progression to taxanes than those with low levels (odds ratio [OR] 3, 95%CI 1.2-7.7, P= 0.016). Moreover, samples from patients treated with abiraterone or enzalutamide before taxanes (51 samples from 43 patients) had significantly higher glutamine levels (T-test, P= 0.014) than those without these prior therapies. Conclusions: Glutamine can be detected in plasma of mCRPC patients and higher levels are associated with adverse clinical outcome, supporting the relevance of metabolism in prostate cancer progression.

TMPRSS2-ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane-resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with prostate-specific antigen (PSA)-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2-2.8) and blood TMPRSS2-ERG detection (HR 2, 95% CI 1.1-3.7) were independently associated to lower PSA-PFS. In patients without prior A/E, blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 3.3, 95% CI 1.4-7.9 and HR 1.8, 95% CI 1.02-3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2-ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2-ERG and prior A/E related to PSA-PFS (p = 0.032) and RX-PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E-cadherin. We conclude that prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r ¼ 0.91) with the ORR following antiPD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low ¼ 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Background Taxanes are the most active chemotherapeutic agents in metastatic castration-resistant prostate cancer (mCRPC), with demonstrated survival benefit. However, patients eventually develop resistance and no predictive molecular biomarkers are clinically available. This study analysed molecular changes associated with cell plasticity in CRPC-cell models resistant to docetaxel (D) and cabazitaxel (CZ), as well as in circulating tumour cells (CTCs) and tumour biopsies from patients with mCRPC treated with taxanes. Methods cDNA microarrays were performed in D and CZ-resistant (DR and CZR) DU-145 and PC-3 cell lines. Differential gene expression of a gene subset was validated by qRT-PCR and Western Blot analyses. Gene expression was evaluated in CTCs enriched samples and tumour samples from 22 and 118 patients, respectively. Results Microarrays analysis revealed a pronounced and intermediate epithelial-mesenchymal transition phenotype in DR and CZR cells, respectively. The penetrance of stem-cell-like and neuroendocrine phenotypes generated by D and CZ-resistance differed in the DR and CZR models. Gene expression changes also occurred in CTCs after taxane treatment. Low expression of ESRP1 in tumour samples predicted lower PSA-progression-free survival (PFS) in D-treated (HR 0.4, 95%CI 0.2-0.7, P Conclusions Molecular changes associated with cell plasticity are different in D or CZ resistance. The EMT profile expression in primary tumour was differentially associated to D or CZ benefit. ESRP1 expression in tumour may be a potential predictive biomarker of different sensitivity to D and CZ. Legal entity responsible for the study Hospital Clinic de Barcelona. Funding Instituto de Salud Carlos III-Subdireccion General de Evaluacion y Fomento de la Investigacion; European Regional Development Fund (ERDF); CERCA Programme/Generalitat de Catalunya; Astellas Pharma S.A; Sanofi. Disclosure N. Jimenez: Travel / Accommodation / Expenses: Sanofi. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Janssen-Cilag; Speaker Bureau / Expert testimony: Bayer. A. Font: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Janssen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astra-Zeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Pierre Fabre. A. Rodriguez-Vida: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer ; Research grant / Funding (institution): Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Astra-Zeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Clovis. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: JohnsonJ Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD ; Advisory / Consultancy: Roche; Advisory / Consultancy: Astra-Zeneca; Speaker Bureau / Expert testimony: Asofarma. C. Suarez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Astellas ; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony: Roche/Genentech; Speaker Bureau / Expert testimony: Astra-Zeneca; Travel / Accommodation / Expenses: Roche. M. Domenech: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Janssen. N. Sala-Gonzalez: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. A. Prat: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Nanostring; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. M. Marin-Aguilera: Travel / Accommodation / Expenses: Bristol-Myers Squibb. B. Mellado: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.

238 Background: Treatment resistance is associated with tumor cells molecular plasticity. In metastatic castration resistant prostate cancer (mCRPC), alterations in androgen receptor (AR) have been described as predictors of shorter response to hormonal treatments. Previously, we associated epithelial to mesenchymal transition (EMT) phenotype with chemotherapy resistance. However, other molecular changes responsible of such resistance should be elucidated. Here, we investigate the effect of taxanes on cell plasticity through in vitro models and in circulating tumor cells (CTCs) from mCRPC patients. Methods: Molecular differences due to taxane-exposure were evaluated in cell models of mCRPC (PC-3 and DU-145 resistant to taxanes). Global gene expression (GE) analysis was performed using Affimetrix GeneChip Human Gene 2.0 arrays. GE related with AR axis, EMT and neuroendocrine (NE) phenotypes was validated by quantitative (qRT-PCR). Clinical validation was performed in CTCs from 24 mCRPC patients collected prior and post taxane-treatment. CTCs enrichment was achieved by Isoflux technology through a personalized combination of EpCAM, CDH2 and PSCA antibodies. Results: GE analysis revealed a different deregulation pattern related to the EMT, NE and AR-related phenotypes in resistant CRPC-cells compared to parental cells. Docetaxel resistance was more associated to an EMT phenotype while cabazitaxel resistance to NE patterns. GE patterns in CTCs at post taxane-treatment showed a common upregulation of AR-related genes compared to pre-treatment collected samples. Moreover, most patients experienced upregulation of EMT and NE markers after treatment, which was more pronounced after docetaxel than cabazitaxel therapy. Conclusions: GE changes related to taxane-resistance observed in pre-clinical models also occur in CTCs. This supports the great value of CTCs to evaluate cell plasticity due to taxanes treatment. Further investigation is ongoing to better characterize cellular plasticity and to improve personalized therapeutic strategies that would enhance better clinical outcomes in mCRPC.

235 Background: TMPRSS2-ERG expression at peripheral blood has been correlated with lower docetaxel benefit. This multicenter study prospectively assessed the role of TMPRSS2-ERG mRNA as a taxane-resistance biomarker in blood and retrospectively in tumors, and explored the impact of prior abiraterone/enzalutamide (A/E) in castration-resistant prostate cancer (CRPC) patients and in vitro. Methods: TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with PSA-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. ERG knockdown, combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Results: In the multivariate analysis prior A/E (HR: 1.833; P = 0.005) and blood TMPRSS2-ERG (HR: 2, 95%CI; 1.1-3.67; P = 0.018) , were independently associated to lower PSA-PFS. In patients without prior A/E, both blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 2.92; P = 0.014 and HR 1.82; P = 0.045, respectively) to taxanes. This was not observed in patients with prior A/E. There was a significant interaction between blood TMPRSS2-ERG detection and prior A/E related to PSA-PFS (P = 0.032) and RX-PFS (P = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced neuroendocrine markers and reduced E-cadherin expression. Conclusions: Prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.

Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

Activated BRAF mutations affecting the mitogen-activated protein kinases (MAPK) pathway are present in 50% of metastatic melanomas. Targeted therapies have been developed to block such mutations (1, 2). There is a risk of other components of the MAPK signalling pathway, such as MEK, being reactivated after the use of BRAF inhibitors (3-5). Given the evidence of drug resistance and side-effects of BRAF inhibitors, combined treatments with BRAF and MEK inhibitors are being tested in clinical trials for metastatic melanoma. Trametinib is one of these MEK inhibitors. Skin toxicities from BRAF inhibitors, such as photosensitivity, palmoplantar keratoderma (PPK) and keratosis pilaris (KP), have been reported (4, 6-11). Also, non-melanoma skin cancers (NMSC) are considered one of the most significant sideeffects (3, 11). We report here the profile of skin toxicities from vemurafenib, dabrafenib alone, or dabrafenib and trametinib combined treatment.

Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response. This case report contributes to the scarce literature on the use of immune checkpoint inhibitors in patients with an underlying autoimmune condition.

Direct stimulation of the antitumor activity of immune system through checkpoint inhibitors (ICIs) has demonstrated efficacy in the treatment of different cancer types. The activity of these antibodies takes place in the immunological synapse blocking the binding of the negative immunoregulatory proteins, thus leading to the finalization of the immune response. Despite having a favorable toxicity profile, its mechanism of action impedes the negative regulation of the immune activity which can potentially favor autoimmune attacks to normal tissues. Renal toxicity has been described in several ICI but not with atezolizumab, an IgG1 monoclonal antibody targeting PD-L1 (programmed death ligand 1), approved by FDA as a second-line therapy for advanced urothelial carcinoma. Here we present a patient with a single kidney and metastatic renal cell carcinoma treated with atezolizumab and bevacizumab combination, with biopsy-proven acute interstitial nephritis, who had a complete resolution of renal dysfunction after steroid therapy.

254 Background: The constitutively active androgen receptor (AR) variant 7 (ARV7) has been associated to AR inhibitors resistance, but its role in taxane-benefit has not been stablished. Moreover, the neutrophil-to-lymphocyte ratio (NLR) has been associated with poor outcome in prostate cancer.The PBMC population may contain circulating tumor cells (CTCs) but is mainly constituted by lymphocytes and monocytes, that also express the AR. Here we studied the expression of ARV7 and AR in peripheral blood mononuclear cells (PBMC) and its correlation with NLR and clinical outcome in mCRPC treated with docetaxel. Methods: ARV7 and AR mRNAs were tested by quantitative reverse-transcription PCR. Baseline neutrophil and lymphocyte values and PBMC samples were prospectively collected before treatment initiation. Patients were stratified according to NLR ratio (low NLR: ≤3; high NLR:>3) and to ARV7/ARFL ratio expression (Maxstat Cutoff 1.99). Correlation between NLR and PSA progression-free (PSA-PFS) and overall survival (OS), were measured from the start of docetaxel treatment and calculated by log rank test. Results: Fifty patients were included:25 (50%) had low NLR. Thirty-eight patients (76%) expressed high ARV7/ARFL. No significant correlation between NLR with ARV7, AR and ARV7/AR was observed. High ARV7/ARF ratio correlated to a better PSA-PFS (median PSA-PFS 7.47; HR 0.38, 95%CI 0.17-0.85; P=0.0179) , but not OS. High NLR was associated to a lower OS [Median OS was 9.2 months versus 30.17 months in those with low NLR (HR 2.19, 95% CI 1.17-4.09, p= 0.01)]. When both parameters were combined, high NLR and low ARV7/ARFL ratio were associated to a worse PSA-PFS in comparison with low NLR and high ARV7/ARFL ratiogroup(median PSA-PFS: 4.9 vs. 7.5; p=0.008 and HR 5.08, 95% CI 1.33-19.41, p= 0.08) and OS (median OS: 7.4 vs. 30.5; p=0.001 and HR 22.79, 95% CI 4.29-121.17, p= 0.00). Conclusions: The combination of low ARV7/ARFL high NLR and ratio evaluated in PBMC prior to docetaxel treatment has a predictive impact on response and survival in mCRPC patients.

Background: TMPRSS2-ERG is a genetic alteration specific of prostate cancer, present in primary tumors and maintained under castration resistant prostate cancer (CRPC) progression. It results in androgen-driven overexpression of ERG, which is involved in resistance to taxanes in preclinical models. In prior work, we found that TMPRSS2-ERG expression in blood correlated with docetaxel resistance in metastatic CPRC. Here, we investigated if TMPRSS2-ERG expression in primary tumors predicts taxanes resistance in CPRC and the potential impact of prior second-line hormonal manipulations with abiraterone (A) or enzalutamide (E). Methods: Patients with metastatic CRPC treated with taxanes were included. Formalin-fixed paraffin-embedded (FFPE) tumors and peripheral blood mononuclear cells (PBMCs) fraction were tested for TMPRSS2-ERG by RT-qPCR. FFPE from hormone-sensitive disease (primary diagnosis) were retrospectively obtained. PBMCs were prospectively collected prior taxane initiation. TMPRSS2-ERG expression was tested by RT-qPCR. TMPRSS2-ERG detection was correlated with taxane response and clinical outcome. Results: A total of 84 tumor samples from 74 patients were included: 65 (87.3%) treated with docetaxel, 19 (25.7%) with cabazitaxel and 10 (13.5%) with both. Forty-six tumor samples (54.7%) were TMPRSS2-ERG+ and 38 (45.2%) TMPRSS2-ERG-. Overall, no correlation between tumor TMPRSS2-ERG expression and taxanes response or clinical outcome was observed. In 42 (50%) samples matched tumor and PBMC samples were available at the time of this analysis: 23 (54.7%) had detectable TMPRSS2-ERG on tissue and 11 (26.2%) on PBMCs fraction. In 27 patients, taxanes were administered as a first-line therapy and in 15 after A or E progression. TMPRSS2-ERG was detected in PBMC from 8 (29.6%) and 3 (20%) patients without or with prior A or E. In patients without prior A or E, TMPRSS2-ERG expression in primary tumors predicted a lower median PSA-PFS (5.5 vs 10.1 months for TMPRSS2-ERG+ vs -, respectively; p Conclusions: The role of TMPRSS2-ERG in taxane resistance may be different according to prior exposure to second-line hormone-therapy in CRPC. Prior androgen receptor inhibition may result in TMPRSS2-ERG downregulation and/or activation of alternative mechanisms of resistance. Further data according to this hypothesis will be presented. Citation Format: Mercedes Marín-Aguilera, Òscar Reig, Natalia Jiménez, Iván Victoria, Lydia Gaba, Sandra López, Javier Prato, Maria Verónica Pereira, Teresa Vilella, Montserrat Domenech, Josep Badal, Albert Font, Juan José García-Mosquera, Olatz Etxaniz, Cristina Carrato, Cristina Suárez, Joan Carles, Fabriccio Racc, Pedro Luis Fernández, Aleix Prat, Begoña Mellado. TMPRSS2-ERG predictive value for taxanes resistance according to prior second-line hormonal manipulations in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2777. doi:10.1158/1538-7445.AM2017-2777

66 Background: Anti-PD1 antibodies (Abs) Nivolumab (Nivo) and Pembrolizumab (Pembro) have both demonstrated to improve the overall survival (OS) in patients (pts) with advanced or metastatic melanoma (MM) in the first line setting. We previously reported that an increase in absolute eosinophil counts (AEC) of 100/mm3 over baseline at week 3 and an AEC > 400/mm3 at week 12 during anti-PD1 treatment (tmt) might identify pts with MM most likely to experience long-term disease control (1). AEC could serve as an important marker allowing the detection of those patients who may benefit from the therapy with anti-PD1 Abs. Methods: This retrospective observational study included pts with MM who received anti-PD1 tmt in a single institution. The objective was to identify whether an increase over the upper limit of normal AEC (>400/mm3) at any time during the tmt could predict better outcomes. Blood tests were performed before every tmt administration. Progression free survival (PFS) and OS were evaluated. Descriptive statistics were used to analyze patient baseline characteristics. PFS and OS were estimated by the Kaplan-Meier method. Results: From March 2013 to February 2016, 50 pts were treated with anti-PD1 Abs (39 pts with Pembro and 11 pts with Nivo). Median age was 58 years (33-84). 72% had received previous systemic tmt for MM, 64% had stage M1c disease, and 50% had elevated LDH levels. BRAF V600 mutations were observed in 34%. The median time to increase AEC > 400/mm2 was 42 (14-196) days. Pts who experienced an increase > 400/mm3 at 12 weeks demonstrated better outcomes in terms of PFS (21,9 [95% CI: 11,1-32,6] vs. 7,5 [95% CI: 4,3-10,7] months, p=0.017) and OS (38,0 [95% CI: 30,8-45,1] vs. 20,5 [95% CI: 15,7-25,3] months, p=0.025) compared with those who did not. Moreover, according to our previous results, pts with an increase of at least 100/mm3 in AEC over the baseline at 12 weeks also showed better OS (32,5 [95% CI: 26,3-38,8] vs. 16,3 [95% CI: 11,1-21,6] months, p=0.008). Conclusions: An increase in AEC of 100/mm3 over baseline and an absolute AEC > 400/mm3 at week 12 during anti-PD1 tmt might identify pts with MM most likely to experience clinical benefit with anti-PD1 Abs which could be relevant for pts management.

The space-time variation of phytoplankton pigments in the western Intra-Americas Sea (IAS), in the vicinity of the island of Cuba, is examined using digital images obtained with the Coastal Zone Color Scanner sensor flown aboard the Nimbus 7 satellite from 1978 to 1986. The results are compared to historical in situ hydrographic observations. A marked seasonality in pigment concentration was observed in waters around Cuba, with an average of 0.07 mg m−3 in summer (April-September) and 0.13 mg m−3 during winter (October–March). The range of variation in pigment concentration was larger in the Gulf of Mexico relative to the western Caribbean Sea. We identified four biogeographical areas on the basis of groups of pixels with similar patterns of time variability. These are area I: southwest of Cuba, Yucatan Channel, and Florida Strait; area II: central Gulf of Mexico; area III: east of Cuba; and area IV: central Caribbean Sea, south of Jamaica and Hispaniola. Two major meteorological events led to anomalies in the seasonal cycle of pigment concentrations. During El Nino-Southern Oscillation (ENSO) of 1982–1983, positive anomalies were observed in the pigment concentration in the western IAS during winter months. This was associated with intense mixing of the water column by higher-frequency and stronger winds associated with cold fronts. ENSO 1982–1983 therefore had a fertilizing effect on the IAS region. Another positive anomaly was observed in 1980–1981, a non-ENSO period that featured higher hurricane and extratropical low-pressure activity.

The Yucatan Current has received very little biological or oceanographic attention in the past, but oceanographers from Cuba, Mexico, and the United States are changing that. They have assembled a multidisciplinary, multinational dataset and are beginning a detailed examination of the current, which has a large impact on all three countries. A series of theoretical and applied studies are using historical infrared and ocean color satellite data and some ship data. In general, western boundaries of large ocean gyres have intense currents along continental margins, and important physical and biological processes take place in such regions. In the northwest Caribbean Sea, such an intense flow is funneled through a constriction known as the Yucatan Strait, between Mexico's Yucatan Peninsula and Cuba (see Figure 1, inset).

3038Background: Anti-PD1/PDL1 drugs show consistent activity across various solid tumors. However, a substantial proportion of patients show primary resistance, and those who benefit do not benefit...

e14552Background: Ipilimumab (Ipi) is an anti-CTLA-4 antibody that has demonstrated to improve survival in patients (pts) with advanced melanoma (MM). The blockade of CTLA-4 may result in a systemi...

A pharmaceutical care programme was implemented at our hospital in early 2013. The main objectives were to analyse and describe the pharmaceutical interventions made, to calculate adherence, interventions and to evaluate patient satisfaction with the care programme. We performed a single-centre descriptive and prospective intervention in cancer patients who received oral chemotherapy as part of a clinical trial in 2013. Eighty-three patients were included. Median age was 58 years (range, 31-80) and 42 patients (50.6%) were men. We recorded 23 interventions, 13 of which were associated with drug interactions. The mean percentage of adherence was 98.9%. The interview with the pharmacist was considered to be very important by 84.6% of the respondents. A total of 92.3% said that they would like to speak to the pharmacist at subsequent visits. The doubts detected during the visits enable us to conclude that the information patients receive with respect to their study medication is usually incomplete. An integrated pharmaceutical care programme for cancer patients participating in clinical trials with oral cytostatic drugs was successful in terms of adherence and patient satisfaction and makes it possible to guarantee the safety and effectiveness of treatment on an individual basis.

Background: ABTL0812 is a first-in-class antitumor drug whose mechanism of action relies on the inhibition of PI3K/Akt/mTOR (PAM) pathway by upregulation of TRIB3 levels, an endogenous inhibitor of Akt activity that prevents Akt phosphorylation. Preclinical studies showed good efficacy of ABTL0812 in xenograft models with high safety margin. Here we describe the First-in-Human (FiH) Phase I/Ib clinical trial of ABTL0812 in patients with advanced solid tumors (NCT02201823). Methods: ABTL0812 was dosed daily, by the oral route, in 28-day cycles. The study included a 4-cohort dose escalation, in a 3+3 dose escalating design, followed by an expansion cohort. The trial objectives were to determine safety and tolerability, to evaluate signs of efficacy, to determine drug pharmacokinetics (PK) in plasma and to analyze inhibition of Akt phosphorylation in platelets by MSD® as pharmacodynamic (PD) biomarker. Pretreatment tumor biopsies were analyzed by next generation sequencing to identify mutations in a panel of 50 cancer-related genes. Results: Fifteen patients were recruited in the escalation part and 14 patients in the expansion cohort (February 2014 to May 2015). No dose-limiting-toxicities were detected and the recommended Phase II was 1300 mg tid based on PK/PD modeling. The median number of previous chemotherapy lines was 2 (range 0-11). The profile of ABTL0812 grade 1-2 related adverse events (AEs) included asthenia, nausea/vomiting and throat burning (34%, 31% and 24% of patients, respectively). Only one case of grade 3-4 AE (elevated hepatic enzymes) appeared. ABTL0812 half-life was short (3-5 h), which supported the increase in the administration schedule from once to twice and finally to three times a day. Biomarker analysis showed inhibition of Akt phosphorylation with increasing doses, with average 90% inhibition in the expansion cohort; furthermore it correlated with C-trough plasma levels. Five patients had stable disease (SD) for at least 16 weeks: 1 endometrial cancer (62 weeks), 1 cholangiocarcinoma (35 weeks, ongoing on Sep 15th, 2015), 2 colorectal cancer (28 and 22 weeks) and 1 lung adenocarcinoma (16 weeks). The median time to progression in the expansion cohort was 11 weeks (range 1-≥35 weeks). Interestingly, the tumor biopsy from the patient with endometrial cancer had activating mutations in Akt1 (E17K) and PIK3CA (R88Q). The tumor from the patient with colorectal cancer (28 weeks SD) showed deleterious mutations in TP53 (R248W) and APC (Q1469Ter). None of these samples included major mutations in Ras. Conclusions: ABTL0812 is a PAM pathway inhibitor acting by a novel mechanism of action that involves upregulation of TRIB3 levels. The FiH Phase I/Ib study in patients with advanced solid tumors showed excellent tolerability and safety profile and demonstrated dose-dependent inhibition of Akt phosphorylation. ABTL0812 treatment induced several long term disease stabilizations (5/29), being the best responder a patient with endometrial cancer (68 weeks) with activating mutations in Akt1 and PIK3CA. Based on these data, a Phase II clinical trial in patients with endometrial cancer is planned. Citation Format: Laura Vidal, Lydia Gaba, Ivan Victoria, Marta Gil-Martin, Berta Laquente, Marc Cortal, Merce Brunet, Pilar Paredes, Mariana Gomez-Ferreria, Jose Alfon, Carles Domenech, Pedro Gascon. First-in-Human Clinical Trial of ABTL0812, a Compound that Inhibits PI3K/Akt/mTOR Pathway by Upregulating TRIB3, in Patients with Advanced Solid Tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C18.

2585 Background: ABTL0812 is a novel drug with reported preclinical activity in several tumor types. In vitro and in vivo assays have shown that ABTL0812 is an inhibitor of the Akt/mTOR pathway by ...

e20030 Background: Limited data exists on the sequencing of BRAF inhibitors (BRAFi) and immunotherapy (IT) in patients (pts) with BRAFV600-mutant metastatic melanoma (BRAFV600MM). The aim of this a...